Protein tyrosine kinases (PTKs) are a class of enzymes that can catalytically transfer a phosphate group from ATP to the tyrosine residue of a protein substrate, and play a role in normal cell growth. Many growth factor receptor proteins work via tyrosine kinases, and affect signal transduction pathways through this process, thereby modulating cell growth. However, under some conditions, these receptors become abnormal due to either mutation or over-expression, cause uncontrolled cell proliferation, lead to tumor growth, and finally result in a well-known disease—cancer. Growth factor receptor protein tyrosine kinase inhibitors play a role in treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth, by inhibiting said phosphorylation process.
Epidermal growth factor receptor (EGFR) is a multifunctional glycoprotein that is widely distributed on the cell membranes of various tissues in human body, and is an avian erythroblastic leukemia viral (v-erb-b) oncogene homolog. Human EGFR/HER1/ErbB-1 and HER2 (human epidermal growth factor receptor-2)/ErbB-2/Teu/p185, HER3/ErbB-3, HER4/ErbB-4 and the like are grouped into the HER/ErbB family, and belong to protein tyrosine kinases (PTKs). Clinical studies show that EGFR and the like are over-expressed in many tumors, for example, epithelial-derived tumors such as squamous cell carcinoma of head and neck, breast cancer, rectal cancer, ovarian cancer, prostate cancer, and non-small cell lung cancer. By competing with ATP for binding kinase catalytic sites in the intracellular region, Pan-HER tyrosine kinase inhibitors block the autophosphorylation of tyrosine in the molecule, block the activation of tyrosine kinase, and inhibit the activation of HER family, thereby inhibiting cell cycle progression, accelerating cell apoptosis, and exerting a therapeutic action.
After binding to ligand, EGFR forms a dimer with a subgroup of HER family, and then binds to ATP to activate the tyrosine kinase activity of EGFR itself, resulting in the autophosphorylation at several tyrosine sites of the intracellular kinase region. Pan-HER tyrosine kinase inhibitors have good effect of inhibiting tumor growth, by acting on EGFR and HER2/4 simultaneously and inhibiting the activation of HER family.
The quinazoline derivative of the following Formula (I), N-(4-((3-chloro-4-fluorophenyl)amino)-7-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methoxy)quinazolin-6-yl)acrylamide (which was disclosed in the patent application WO2012027960A1), is an irreversible Pan-HER tyrosine kinase inhibitor, can effectively inhibit EGFR, and also has an inhibitory effect on HER2/4. The drug having an irreversible inhibitory effect on HER/ErbB family can not only enhance the activity of drugs, but also can reduce the generation of drug resistance, and has a significantly inhibitory effect on erlotinib-resistant H1975 cell line.

Development of crystals is very important in drug development. Different forms of a compound have different bioavailability and solubility. Crystal forms have a great influence on the stability, processing property, bioavailability, solubility, formulation, and industrial production and transportation of compounds.